Focused Ultrasound (FUS), in conjunction with microbubbles, remains the sole technique that can induce localized BBB opening noninvasively and regionally. Intranasal (IN) administration has emerged as a promising approach for drug delivery to the brain. Traditionally, it has been successfully used as a convenient method for drug delivery to the systemic circulation, because IN administered drugs can be absorbed through a rich vascular network in the nasal cavity into the systemic circulation. Although most drugs absorbed into the blood circulation cannot enter the brain parenchyma because of the BBB, it has been demonstrated feasible in animal and clinical studies that drugs can be directly delivered from the nose to the brain, bypassing the BBB. Over the past few years, our team has shown that the BBB can be reproducibly opened using FUS and intravenously (IV)-administered microbubbles in a specific subcortical region associated with neurodegenerative disease. Molecules on the order of 0.5 kDa-4 MDa, including Dextran, neurotrophic factors and viral vectors, have been shown to be successfully delivered and localized within the intracellular space of neurons triggering signaling pathways within the neuronal cell. In this study, we hypothesize that the BBB opening can be applied entirely noninvasively (i.e., injection-free) while reducing the risk of systemic toxicity. FUS and intranasal delivery are therefore combined for the first time for enhancing the delivery efficiency of intranasally administered drugs to a targeted region while nanodroplets (ND) substitute microbubbles due to their smaller size that should facilitate intranasal delivery (FUS+IN+ND). We propose to develop an entirely noninvasive approach for trans-BBB deliver that offers the advantages of 1) an injection- free approach due to the intranasal (inhalation) administration , 2) higher selectivity due to the nanodroplet vehicle used and 3) lower toxicity due to both intranasal and nanodroplet approaches. The specific aims are thus to: 1) demonstrate feasibility of BBB opening using nanodroplets administered intranasally; 2) demonstrate efficacy of facilitating protein and gene therapy in a Parkinsonian mouse model. Intranasal delivery of both the vehicle (nanodroplet) and the drug (protein or virus) in combination with FUS could provide an entirely noninvasive, more targeted and less toxic alternative to the currently used methodologies facilitating thus clinical translation and acceptance.